Highly Regioselective, Acid-Catalyzed, Three ... - ACS Publications

Jan 17, 2019 - continuous synthetic drive for novel and better synthetic strategies ... the further application of a diversity oriented synthesis. The...
0 downloads 0 Views 361KB Size
Subscriber access provided by Stockholm University Library

Letter

Highly Regioselective, Acid Catalyzed, Three-Component Cascade Reaction for the Synthesis of 2-aminopyridine-Decorated Imidazo[1,2-a]pyridine Qiu-Xing He, Yao-Feng Liang, Chang Xu, Xiao-Kun Yao, Hua Cao, and Hua-Gang Yao ACS Comb. Sci., Just Accepted Manuscript • DOI: 10.1021/acscombsci.8b00149 • Publication Date (Web): 17 Jan 2019 Downloaded from http://pubs.acs.org on January 21, 2019

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 10 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Combinatorial Science

Highly Regioselective, Acid Catalyzed, Three-Component Cascade Reaction

for

the

Synthesis

of

2-aminopyridine-Decorated

Imidazo[1,2-a]pyridine Qiu-Xing He,a, * Yao-Feng Liang,a Chang Xu,a Xiao-Kun Yao,a Hua Cao a and Hua-Gang Yao,a, * a

School of Chemistry and Chemical Engineering and Guangdong Cosmetics Engineering &

Technology Research Center, Guangdong Pharmaceutical University, Zhongshan 528458, China

ABSTRACT: A highly regioselective acid-catalyzed three-component reaction of 2-aminopyridine and 3-phenylpropiolaldehyde for the construction of imidazo[1,2-a]pyridine has been developed. This strategy provides a broad range of substrates and represents an efficient approach to give various 2-aminopyridine-decorated imidazo[1,2-a]pyridine in good yields. KEYWORDS: Pivalic acid, 2-aminopyridine, three-component reaction, imidazo[1,2-a] pyridine

Considerable efforts have been devoted to developing new Imidazo[1,2-a]pyridine-based heterocycles compounds1-4, that is, a single compound that displays the coexistence or synergism of two or more properties including obvious inhibitory effects on many target enzymes5-7 and good bioactivity in the aspect of anti-tumor8-12, anti-virus13-15, anti-bacterial16-18, anti-tuberculosis19,20, anti-inflammatory21, antiulcer22, anti-diabetic23, antipsychotic24,25, etc. 3-Substituted imidazo[1,2-a]pyridines are of particular interest, because of their potential applications in many commercially available drugs such as necopidem, alpidem, saripidem, minodronic acid. The versatility and value of these Imidazo[1,2-a]pyridine derivatives for a wide range of applications feeds the continuous synthetic drive for novel and better synthetic strategies, including oxidative cross-coupling, multi-component reaction26-34. Despite the fact that much progress has been made in the synthesis of these derivatives, there still remains great challenges for synthetic organic chemists in developing a facile approach for the direct synthesis of 3-2-aminopyridine-decorated imidazo[1,2-a]pyridines. For example, Mareev35 et al. first reported the synthesis of 3-[2-pyridylamino(phenyl) methyl]imidazo[1,2-a]pyridine by employing phenylpropynal and 2-aminopyridine (Scheme 1, a). Unfortunately, only one product has been synthesized under their protocol. Subsequently, we disclosed an efficient one-pot methodology for the synthesis of these compounds via AcOH catalysis (Scheme

ACS Paragon Plus Environment

ACS Combinatorial Science 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 2 of 10

1, b) and a series of imidazo[1,2-α]pyridines were obtained in high to excellent yields36. However , there are still some limitations and inconveniences of this protocol. The substituted pyridine-2-amine used to undergo a Michael type addition to finish the transformation should be the same as the one reacted with the aldehyde to form the imine intermediate during the first step of the reaction. This seriously restricted the further application of a diversity oriented synthesis. Therefore, the development of new catalytic systems to achieve two different 2-aminopyridine reactions for the direct construction of multifunctional imidazo[1,2-a]pyridines is still of great importance. In this context, our group envisions to construct 2-aminopyridine-decorated imidazo[1,2-a]pyridine derivatives via a three-component reaction of 2-aminopyridines and 3-phenylpropionaldehyde.

Scheme 1

Syntheses of N-(imidazo[1,2-a]pyridin-3-yl(phenyl) methyl)2-aminopyridine

(a) Mareev et al. work:

N

Ph

CHO

NH2

5 mol% HCl MeCN 25 oC

+

H N

N

N N only one example

Ph (b) Our previous work: R1

R

CHO AcOH CH3CN

+ N

NH2

1

N

o

80 C 8 h

R1

N N

R1

R

H N

R = Cl, CF3 (c) This work: R

CHO R

1

+ N

NH2

R + NH2 2

N

R1 R

N

H N

R2

N N

In the beginning, the model reaction of 2-amino-3-methylpyridin 1{1}, 5-(trifluoromethyl)-2-aminopyridine 1{5} and 3-phenylpropiolaldehyde 2{1} were conducted to determine the suitable reaction conditions37. The results are described in Table 1. The desired product 3{1,5,1} was not obtained without any catalysts in dioxane at room temperature (entry 1). We then attempted to increase the yield of product 3{1,5,1} by adding variety of catalysts. Using 5 mol % PivOH in dioxane at room temperature afforded a yield of 42% (entry 2), but the addition of benzoic acid,

ACS Paragon Plus Environment

Page 3 of 10 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Combinatorial Science

AcOH, TsOH, TFA, ZnCl2, FeCl3, FeCl2, showed that the product 3{1,5,1} was formed in relatively lower yield or not detected (entries 3-10). It is interesting to note that the temperature changes significantly affect the yield. The results indicated that the reaction at 60 °C was the most suitable (entry 2, 9-13). In order to improve the reaction efficiency, we evaluated the influence of various solvents. Among the solvents, we were delighted to find that the product 3{1,6,1} was readily formed in 92 % yield in CH2Cl2. Other solvents, such as DMSO, DMF, or toluene, did not lead to any improved result (entries 14-19). Table 1.

Optimization of the reaction conditionsa

NH2 F3C N 1{1}

Entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19

+

NH2 N

CHO

+ Ph 2{1}

1{5}

Catalyst PivOH Benzoic Acid AlCl3 AcOH TsOH TFA ZnCl2 FeCl3 FeCl2 PivOH PivOH PivOH PivOH PivOH PivOH PivOH PivOH PivOH

N

solvent, N2, 8 h

N

Solvent 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane DMSO DMF CH2Cl2 toluene DCE THF

N

Ph

catalyst, temp

T (oC) rt rt rt rt rt rt rt rt rt rt 60 80 100 60 60 60 60 60 60

a Reaction

CF3

N H 3{1,5,1}

Yield b (%) N.P. 42 28 30 14 17 14 trace trace N.P. 67 65 64 23